1. Field of Invention
This application relates to anti-inflammatory agents, and in particular to the use of cannabinoids for the treatment of inflammatory diseases such as rheumatoid arthritis, multiple sclerosis and Crohn""s Disease, and to medicinal preparations containing cannabinoids.
2. Background Art
Cannabis sativa, commonly known as marijuana, has been used for several years for its medicinal effects, including antipyretic and analgesic properties. Approximately 80 cannabis constituents, termed cannabinoids, naturally occur as 21 carbon atom compounds of cannabis and analogues of such compounds and their metabolites [Mechoulam, In xe2x80x9cMarijuna Chemistry, Metabolism and Clinical effects, Academic Press, New York (1973), pages 1-99].
The major psychoactive component of marijuana is Delta-9-tetrahydrocannabinoid (THC), which has been widely studied. Studies have shown that THC affects growth, development and reproductive activity [Pharmacol Rev. 38 (1986), pages 1-18 and 151-178; Marihuana, Pharmacological Aspects of Drug Dependence, Springer Verlag (1996), pages 83-158]. Studies in mice have shown that THC suppresses antibody formation against sheep red blood cells and causes changes in cytokine production. In vitro studies, however, have shown that THC may suppress or enhance (depending on dosage) the production of various cytokines such as IL-1, IL-6 and TNFxcex1 by leukocytic cells.
Cannabidiol (CBD) is present in most cannabis preparations (hashish, marijuana, ganja) in higher concentrations than THC. Cannabidiol. was, first isolated in 1940 by Todd and Adams [J. Amer. Chem. Soc., 6,2 2194 (1940), J. Chem. Soc., 649 (1940)]. Its structure was elucidated by Mechoulam and Shvo in 1963 [Tetrahedron, 19 (1963), page 2073]. Its absolute stereochemistry was determined in 1967 [Tet. Lett., 1109-1111 (1967)]. The synthesis of cannabidiol in its racemic form and its natural form were reported in the 1960""s [J. Amer. Chem. Soc., 87, 3273-3275 (1965), Helv. Chim. Acta, 50 719-723 (1967)].
Cannabidiol has no psychotropic (cannabimimetic activity) and does not bind either the brain or the peripheral receptors, CB1 and CB2 respectively [Science 169, 611-612 (1970); xe2x80x9cMarijuana/cannabinoids: neurobiology and neurophysiologyxe2x80x9d, ed. L. Murphy and A. Bartke, CRC Press, Boca Raton, 1-33 (1992)]. Cannabidiol has, however, been observed to have anticonvulsant effects [Pharmacol, 124, 141-146 (1982)]. Cannabidiol has also been effective in animal models predictive of antipsychotic activity, and has been found to have antipsychotic effects in the, case of schizophrenia [Psychopharmacol., 104, 260-264 (1991); J. Clin. Psychiatry, 56 485-486 (1995)].
Cannabidiol has sporadically been studied for its immunomodulatory effects in vivo and in vitro. Smith et al [Proc. Soc. Exp. Bio Med. 214 (1997), pages 69-75] demonstrated that BALB/C mice injected with cannabidiol did not show significant change in the level of mRNA of IL-1, IL-6 and TNFxcex1. At an 8 mg/kg dose of cannabidiol, the mortality of mice sublethally injected with Legionella was not affected.
Preliminary studies by Formukong et al [Inflammation, 12, 361-371 (1988)] showed that cannabidiol inhibited PBQ-induced writhing in mice when given orally at doses up to 10 mg/kg. Cannabidiol was also shown to reduce TPA-induced erythema, which is dependent upon prostaglandin release, in mice when applied topically.
In an in vitro study, Coffey et al [Biochem. Pharmacol, 52 (1996), pages 743-51] demonstrated that THC and cannabidiol inhibited nitric oxide (NO) produced by mouse peritoneal macrophages activated by LPS and IFNxcex3. Watzl et al [Drugs of Abuse, Immunity and Immunodeficiency, Plenum Press, New York, .63-70 (1991)] studies in vitro the effects of THC and cannabidiol on secretions of IL-1, IL-2, IL-6, TNFxcex1 and IFNxcex3 by human leukocytes following activation by mitrogen, They found that both cannabinoids in low concentrations increase IFNxcex3 production, whereas in high concentrations (5-24 xcexcg/ml) completely blocked IFNxcex3 synthesis, and cannabidiol decreased both IL-1 and TNFxcex1 production and did not affect IL-2 secretion.
The inventors have now unexpectedly found that cannabinoids may be used to treat inflammatory diseases, such as rheumatoid arthritis and Crohn""s disease. Inflammatory diseases involve the complex interaction between several components such as Interleukins (IL-1, IL-6 and IL-8), TNF-xcex1 and various mediators such as nitric oxide, ROI and PGE2.
Cannabinoids have been found by the inventors to act as anti-inflammatory agents in vivo.
Accordingly, a first aspect of the invention provides use of one or more cannabinoids as an anti-inflammatory agent.
Preferably, the cannabinoid is an isolated cannabinoid such as cannflavone-2 (formula I) or a cannabinoid having the general formula II. 
where:
R1 is a straight or branched chain saturated or unsaturated alkyl having preferably 2 to 6 carbon atoms, especially 5 carbon atoms;
R2 is H or a saturated or unsaturated straight, branched or cyclic hydrocarbon group, or forms a substituted or unsubstituted cyclic ether with the O atom at the sixth position.
Especially preferred cannabinoids are: 
The term isolated is intended to include a naturally occurring cannabinoid which has been purified from a natural source or one which has been chemically synthesised.
Preferably the cannabinoid is used as an anti-inflammatory agent against inflammatory diseases, especially rheumatoid arthritis or Crohn""s Disease, sarcoidosis, asthma, Alzheimer s disease, multiple sclerosis, Psoriasis, ulcerative colitis, osteoarthritis or spondyloarthropathy (erg. ankylosing spondylitis).
The invention also provides a method of treating a patient suffering from an inflammatory disease comprising the step of administering to the patient a pharmaceutically acceptable amount of a cannabinoid.
The cannabinoid is preferably as defined above.
The patient is preferably a mammal such as a human.
Cannabinoids may be used separately or as mixtures of two or more cannabinoids. They may be combined with one or more pharmaceutically acceptable compounds such as carriers.
The invention also provides the use of one or more cannabinoids as previously defined in the manufacture of a medicament to treat inflammatory diseases.
A further aspect of the invention provides a method of treating an inflammatory disease comprising the step of administering to a patient one or more cannabinoids as previously defined. The cannabinoids may for example be applied orally, intramuscularly, subcutaneously, intradermally, intravenously, by nasal spray or topically.
As a general proposition, the total pharmaceutically effective amount of cannabinoid administered will be in the range of 1 xcexcg/kg/day to 50 mg/kg/day of patient body weight, preferably 2.5 to 10 mg/kg/day especially 5 mg/kg/day.
Accordingly. the invention also relates to medicinal preparations, including topical formulations, capsules, tablets and/or injectable formulations, containing one or more cannabinoids as previously defined for use as anti-inflammatory agents.
Preferably the cannabinoids, according to any previous aspect of the invention, are used or combined with one or more known anti-inflammatory compounds, especially anti-rheumatoid arthritis compounds, such as methotrexate. This allows advantageous properties of the cannabinoids to be combined with known properties of the known compound(s).
The invention will now be described by way of example only with reference to the figures in which: